Recent work from our laboratories and others has shown that the LKB1 (STKII) tumor suppressor gene is frequently inactivated (through deletions or point mutations) in a wide variety of human cancers. Although Lkb1 inactivation facilitates tumor progression by enhanced invasion and metastasis and therefore appears to be an adverse prognostic feature, the mechanisms whereby Lkb1 deficiency promotes tumorigenesis are poorly understood at the molecular level. Our current understanding of Lkb1 suggests that it acts in part through the AMPK and mTOR pathway, but there is strong evidence that Lkb1 also acts through alternative parallel pathways that remain to be elucidated. Consequently, our ability to exploit Lkb1 deficiency to develop new targeted therapies is rather limited. This proposal represents a joint effort by four investigators with complementary areas of expertise and an established track record of productive collaborations in the areas of Lkb1 biology, mouse cancer models, and translational cancer research. We will refine faithful murine Lkb1-based genetic models we have already developed of pancreatic adenocarcinoma, non-small cell lung cancer, uterine cancer, and melanoma. These murine models will be used to 1) study the mechanisms whereby Lkb1 regulates tumor progression; 2) identify biomarkers expressed by Lkb1-deficient cancers and explore their utility as predictors of adverse outcomes and therapeutic responses in humans, taking advantage of our existing banks for the above tumors; and 3) develop and test novel therapeutic agents and strategies against Lkb1-deficient cancers. These models will employ state-of-the-art conditional and somatic inactivation strategies, and combine Lkb1 deficiency with other established oncogenic driver events well-studied in the four laboratories. These efforts will leverage the unique strengths of the four participating institutions in molecular biology, small animal imaging, comparative pathology, pharmacology, and experimental therapeutics. This research will lead to an enhanced understanding of the role of Lkb1 inactivation in a variety of neoplasms, and translate this new understanding into novel predictive biomarkers and therapeutic approaches.